Two thirds of all breast cancers diagnosed in US women express estrogen and/or progesterone receptors. Although 5 years of tamoxifen had long been the standard adjuvant hormonal therapy for women with early- stage, hormone receptor-positive breast cancer, the aromatase inhibitors (AI's) have rapidly supplanted tamoxifen as the hormonal therapy of choice. Several large adjuvant trials have demonstrated that using an AI in place of or after tamoxifen reduced the risk of breast cancer recurrence, as compared to treatment with 5 years of tamoxifen. A recent American Society of Clinical Oncology expert consensus panel recommended that all postmenopausal women with early-stage, hormone-receptor-positive breast cancer receive an AI as part of their adjuvant therapy. However, long term data regarding the safety and toxicity of AIs is largely lacking. Data from the large adjuvant trials evaluating the use of the AI's indicate that arthralgia is one of the major toxicities associated with AI therapy and one of the most common reasons for AI treatment discontinuation. There has been little data regarding effective treatments for arthralgias. In addition to arthralgia, other bone-related adverse effects of AI therapy include bone loss and fractures. Although medications such as bisphosphonates can be used to alleviate bone loss, these drugs also cause significant side effects. Given the efficacy of the AI's, it is essential that better ways to manage the toxicity of these agents be explored. Nonpharmacologic methods of managing the side effects of the AI's are especially desirable. Exercise has been shown to improve bone metabolism in healthy women, and to be beneficial for people with fibromyalgia, osteoarthritis and rheumatoid arthritis;however, no randomized trial has examined the impact of exercise on arthralgia or bone mass in breast cancer survivors taking AIs. In the proposed trial, we plan to evaluate the ability of a walking and strength training exercise program to attenuate side effects of AI therapy. Our trial will randomize 180 postmenopausal breast cancer patients, who have been taking an AI for at least 6 months and are currently experiencing at least mild arthralgia which started after initiating AI therapy, to a yearlong exercise intervention or to an attention control group. We will then examine the impact of exercise on severity of arthralgia, factors mediating the effect of exercise on arthralgia, and other side effects of AI therapy including endocrine-related quality of life and bone mineral density. Women will be randomized to a home- and gym-based exercise program or attention control (health education) group. Women randomized to exercise will participate in 150 min/wk of aerobic exercise and a twice-weekly strength training program. We will conduct baseline, 6- and 12-month clinic visits, as well as 3- and 9-month mailings to evaluate the effect of the intervention on study outcomes. Given the widespread use of the AI's, we believe that our approach is innovative and timely. If our intervention is able to alleviate AI-associated side effects and reduce the number of women who prematurely discontinue them, we believe that our study may prove beneficial for the large number of postmenopausal women diagnosed with hormone receptor-positive breast cancer each year. Our study will also be especially relevant to the mission of NCI and the Office of Cancer Survivorship to improve the quality of life for cancer survivors, support intervention survivorship research, and to ensure best practices for addressing the health needs of survivors. PUBLIC HEALTH RELEVANCE: A recent American Society of Clinical Oncology expert consensus panel recommended that all postmenopausal women with early-stage, hormone-receptor-positive breast cancer (~2/3 of all women diagnosed with breast cancer) receive an aromatase-inhibitor (AI) as part of their adjuvant therapy. Data from the large adjuvant trials evaluating the use of the AI's indicate that arthralgia and bone loss are the major toxicities associated with AI therapy and the most common reasons for AI treatment discontinuation. Our trial will examine the impact of an exercise program on alleviating AI-associated side effects such as arthralgia, bone mineral density, and endocrine-related quality of life, and may prove beneficial for the large number of postmenopausal women diagnosed with hormone receptor-positive breast cancer each year.